<p>  </p> <p>Conventional clinical therapies for head and neck squamous cell carcinomas (HNSCC) include surgical resection, chemotherapy (CT), and radiotherapy (RT). For locally advanced HNSCC, the CT-RT combination (“chemoradiation”) has been shown to be more effective than CT or RT alone and is the current standard of care. A novel radiation-controlled drug release nanoparticle formulation has been developed to realize the maximum benefits of intratumoral CT-RT. Under the application of low-dose X-ray, the formulation is capable of releasing PTX and providing localized, controlled, and sustained drug release for improvements in therapeutic efficacies.</p>

<div>Under the guidance of cancer treatment data, this thesis emphasizes the development of radiation-responsive nanomaterials for the effective implementation of localized, multimodal therapy for solid tumors. Evidence from decades of treatment outcomes underscores the benefits provided by employing multiple therapeutic agents in concert to improve prognoses for cancer patients. As a pillar of standard care in oncology, radiation therapy (RT) is a particularly appropriate choice as a component of combination therapies, acting as a localized tool for achieving long-term tumor control. By combing primary RT with radio-sensitizing, polymer-encapsulated formulations of crystalline calcium tungstate nanoparticles (CWO NPs), this work has shown significant improvements in efficacy in in vitro and murine xenograft models of primary human head and neck tumors as well as in spontaneous sarcoma in a clinical case study. Under X-ray radiation, CWO NPs emit long-wavelength ultraviolet (UV-A) and visible light, a property referred to as radioluminescence. This work focuses on utilizing these properties in combination with encapsulant functionalization strategies to further improve therapeutic outcomes through specific mechanistic enhancements.</div><div><br></div><div>Ordinarily used primarily to improve biocompatibility and colloidal stability, the polymeric materials used to encapsulate the CWO NPs were tailored to serve distinct functions in the overall combination therapy scheme. Approaches explored in this work include surface functionalization of these polymers with a cancer-specific ligand, folic acid, and the incorporation of photo-responsive/sensitizing bilirubin-polymer conjugates as an encapsulant. The predicted outcomes of surface functionalization and photo-active encapsulation were confirmed to significantly enhance radiotherapy efficacy. Finally, exploration of intratumoral NP distribution after dose administration was conducted to preliminarily evaluate strategies for dose homogeneity improvement. Mechanical agitation of the injection site somewhat improves distribution of NPs in tumor xenografts but requires future exploration for improved understanding and implementation.</div>